The role of CXCL12 in the organ-specific process of artery formation

Abstract

CXC chemokine ligand 12 (CXCL12; stromal cell-derived factor-1 [SDF-1]/pre-B-cell growth-stimulating factor [PBSF]) and its receptor CXCR4 are essential for vascularization in the gastrointestinal tract as well as B lymphopoiesis and colonization of bone marrow by hematopoietic cells. However, the mechanism by which CXCL12/CXCR4 functions in blood vessel formation remains elusive. Here, we have found a novel mode of organ vascularization and determined the roles of CXCL12 in these processes. In the developing small intestine, many short interconnecting vessels form between larger superior mesenteric artery (SMA) and the neighboring primary capillary plexus surrounding the primitive gut, and they elongate and become the arteries supplying the small intestine. Mice lacking CXCL12 or CXCR4 lack the interconnecting vessels but have normal venous networks. The mutants lack filopodial extension and intussusception from endothelial cells of SMAs seen in wild-type embryos. CXCR4 is specifically expressed in arteries in the developing mesenteries and its expression is severely reduced in CXCL12 ؊/؊ embryos.Mice in which CXCR4 is specifically deleted in the endothelium reveal vascular defects identical to those observed in the conventional CXCR4 ؊/؊ embryos. Together, CXCL12 acts on arterial endothelial cells of SMA to up-regulate CXCR4 and mediate the connection between the larger artery and neighboring capillary plexus in an organ-specific manner. IntroductionVascularization of organs generally occurs during embryogenesis by remodeling of the preexisting vascular system to enable them to perform their specific functions. Early in development, embryos form a primary capillary plexus and major vessels, including the aorta and major veins, by a process referred to as vasculogenesis in which endothelial cells differentiate, proliferate, and aggregate. [1][2][3] The vasculature of organs is thought be generated by 2 processes, sprouting or nonsprouting angiogenesis from the primary plexus or major vessels. 1 Sprouting angiogenesis is a process in which capillaries sprout from preexisting vessels into avascular tissues and occurs most frequently late in organogenesis, for example in the brain and kidney. 1,3 Nonsprouting angiogenesis is a process of splitting preexisting vessels by transcapillary intussusceptive pillars and has been reported to be predominant in the embryonic lung. 4 Recent genetic approaches have provided a valuable starting point in probing the molecular mechanisms of vascular development. Mutant analysis of receptor tyrosine kinases and their ligands (such as Flk-1, Flt-1, VEGF-A, Tie1, Tie2, angiopoietin-1, EphB4, and ephrinB2) has indicated that these molecules are essential for early and general vascular development. [1][2][3]5 However, most of these mutations result in early embryonic lethality, which hampers the analysis of the formation of most organ systems at later embryonic stages. Thus, despite years of investigation, the cellular and molecular mechanisms controlling organ vascularization remain...

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

“…Accumulating evidence derived from mice deficient in SDF-1 and CXCR4, in addition to in vitro biochemical and migration studies, have set forth the concept that the SDF-1-CXCR4 pathway has a crucial role in modulating the trafficking and proper engraftment of hematopoietic stem cell (HSCs) and reconstitution of hematopoiesis [7]. The crucial roles of SDF-1 and CXCR4 in embryonic vasculogenesis are demonstrated by the blood vessel abnormalities manifested in SDF-1 −/− and CXCR4 −/− mice [8]. Indeed, the expression of SDF-1 in a large number of tumors and injured tissues strongly suggests that activation of CXCR4 participates in promoting neo-angiogenesis (Table 1).…”

Forkhead transcription factors regulate expression of the chemokine receptor CXCR4 in endothelial cells and CXCL12-induced cell migration

“…As such, the CXCR4 receptor is detected in various types of cells, including hematopoietic and vascular endothelial cells, while it is important to note that CXCR4 expression in endothelial cells of the developing embryo is restricted to arteries such as the dorsal aorta and mesenteric arteries [2,7]. Previous studies also demonstrate the function of the CXCR4-CXCL12 pathway in the process of angiogenesis such as endothelial cell migration and capillary tube formation [8][9][10][11][12].…”

“…The CXCR4-CXCL12 chemokine axis is required for normal development of the cardiovascular, hematopoietic, gonadal and nervous systems [1][2][3][4][5][6]. As such, the CXCR4 receptor is detected in various types of cells, including hematopoietic and vascular endothelial cells, while it is important to note that CXCR4 expression in endothelial cells of the developing embryo is restricted to arteries such as the dorsal aorta and mesenteric arteries [2,7].…”

“…Previous studies also demonstrate the function of the CXCR4-CXCL12 pathway in the process of angiogenesis such as endothelial cell migration and capillary tube formation [8][9][10][11][12]. Several extracellular signals and transcriptional factors such as CXCL12, vascular endothelial growth factor (VEGF), hypoxia and NF-κB have been shown to induce CXCR4 expression in different cell types, including monocytes, cancer cells and endothelial cells [2,10,11,[13][14][15][16][17]. However, the molecular basis of transcriptional regulation of CXCR4, in particular in vascular endothelial cells, is still not fully understood.…”

Adipose-derived stem cells-seeded bladder acellular matrix graft-silk fibroin enhances bladder reconstruction in a rat model

“…The role of this pathway in embryonic vasculogenesis has also been demonstrated, as SDF-1α and CXCR4 doubleknockout mice exhibit severe blood vessel abnormalities [32]. Activation of the ERK 1/2 and AKT pathways is known to be involved in CXCR4-mediated angiogenesis.…”